Cytoprotection by fructose and other ketohexoses during bile salt-induced apoptosis of hepatocytes

Toxic bile salts cause hepatocyte necrosis at high concentrations and apoptosis at lower concentrations, Although fructose prevents bile salt-induced necrosis, the effect of fructose on bile salt-induced apoptosis is unclear, Our aim was to determine if fructose also protects against bile salt-induced apoptosis, Fructose inhibited glycochenodeoxycholate (GCDC)-induced apoptosis in a concentration-dependent manner with a maximum inhibition of 72% +/- 10% at 10 mmol/L, First, we determined if fructose inhibited apoptosis by decreasing adenosine triphosphate (ATP) and intracellular pH (pH(i)), Although fructose decreased ATP to <25% of basal values, oligomycin (an ATP synthase inhibitor) did not inhibit apoptosis despite decreasing ATP to similar values, Fructose (10 mmol/L) decreased intracellular pH (pH(i)) by 0.2 U, However, extracellular acidification (pH 6.8), which decreased hepatocyte pH(i) 0.35 U and is known to inhibit necrosis, actually potentiated apoptosis 1.6-fold, Fructose cytoprotection also could not be explained by induction of bcl-2 transcription or metal chelation. Because we could not attribute fructose cytoprotection to metabolic effects, alterations in the expression of bcl-2, or metal chelation, we next determined if the poorly metabolized ketohexoses, tagatose and sorbose, also inhibited apoptosis; unexpectedly, both ketohexoses inhibited apoptosis, Because bile salt-induced apoptosis and necrosis are inhibited by fructose, these data suggest that similar processes initiate bile salt-induced hepatocyte necrosis and apoptosis, Ln contrast, acidosis, which inhibits necrosis, potentiates apoptosis, Thus, ketohexose-sensitive pathways appear to initiate both bile salt-induced cell apoptosis and necrosis, whereas dissimilar, pH-sensitive, effector mechanisms execute these two different cell death processes.